Faculty Collaboration Database

Cocaine Use Reverses Striatal Plasticity Produced During Cocaine Seeking. Biol Psychiatry 2017 Apr 01;81(7):616-624

Date

11/14/2016

Pubmed ID

27837917

Pubmed Central ID

PMC5346331

DOI

10.1016/j.biopsych.2016.08.033

Scopus ID

2-s2.0-85014531245 (requires institutional sign-in at Scopus site)   27 Citations

Abstract

BACKGROUND: Relapse is a two-component process consisting of a highly motivated drug-seeking phase that, if successful, is followed by a drug-using phase resulting in temporary satiation. In rodents, cue-induced drug seeking requires transient synaptic potentiation (t-SP) of cortical glutamatergic synapses on nucleus accumbens core medium spiny neurons, but it is unknown how achieving drug use affects this plasticity. We modeled the two phases of relapse after extinction from cocaine self-administration to assess how cocaine use affects t-SP associated with cue-induced drug seeking.

METHODS: Rats were trained to self-administer cocaine (n = 96) or were used as yoked-saline control animals (n = 21). After extinction, reinstatement was initiated by 10 minutes of cue-induced drug seeking, followed by 45 minutes with contingent cocaine access, after which cocaine was discontinued and unreinforced lever pressing ensued. Three measures of t-SP were assayed during reinstatement: dendritic spine morphology, alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) to N-methyl-D-aspartate (NMDA) ratios, and matrix metalloproteinase activity.

RESULTS: We found that cocaine use for 10 minutes collapsed all three measures of cue-potentiated t-SP back to baseline. Moreover, when cocaine use was discontinued 45 minutes later, dendritic spine morphology and AMPA to NMDA ratios were restored as animals became motivated to engage unrewarded lever pressing. Nonreinforced drug seeking was positively correlated with changes in spine morphology, and cocaine access reversed this relationship.

CONCLUSIONS: Using a novel modification of the reinstatement paradigm, we show that achieving cocaine use reversed the synaptic plasticity underpinning the motivation to seek the drug.

Author List

Spencer S, Garcia-Keller C, Roberts-Wolfe D, Heinsbroek JA, Mulvaney M, Sorrell A, Kalivas PW

Author

Constanza Garcia Keller PhD Assistant Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Cocaine
Cues
Dendritic Spines
Drug-Seeking Behavior
Extinction, Psychological
Male
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Models, Neurological
Motivation
Neuronal Plasticity
Nucleus Accumbens
Rats
Rats, Sprague-Dawley
Receptors, AMPA
Receptors, N-Methyl-D-Aspartate
Recurrence
Self Administration